Succinimido-(3,4-b)indan-8-ones and process



United States Patent Oflice 3,453,287 Patented July 1, 1969 3,453,287SUCCINlMIDO-[3,4-b]INDAN-8-0NES AND PROCESS Ernest E. Campaigne, 1240 E.Wylie St., Bloomington, Ind. 47401, and Richard F. Weddleton, Scotia,N.Y. (2223 Van Rensselaer Drive, Schenectady, N.Y. 12309) No Drawing.Filed Feb. 9, 1966, Ser. No. 526,047

Int. Cl. A61k 27/00; C07d 27/10 US. Cl. 260-3265 6 Claims ABSTRACT OFTHE DISCLOSURE This invention relates to the provision of a new class oforganic compounds for use as chemical intermediates and as the activecomponent of pharmaceutical compositions. It relates further to aprocess by which the new compounds of this invention can be prepared.

It is an object of the present invention to provide a new class ofl-unsubstituted Zia-substituted succinimido- [3,4-b]-'indan-8-ones andmetal salts thereof which can be used as intermediates and reagents inthe preparation of other organic compounds and as therapeutically activecomponents of pharmaceutical compositions. It is a further object of thepresent invention to provide a process by which said compounds can beprepared. Other objects will be apparent from a reading of the ensuingdescription of the present invention.

In accordance with the present invention, the foregoing objects areaccomplished by the provision of a class of compounds of the formula:

and the salts, especially the pharmaceutically acceptable salts thereof.In Formula I the symbol R is intended to means lower alkyl of l-8carbons or phenyl; and the symbol R is intended to represent hydrogen,chloro, bromo, iodo, fluoro, trifluoromethyl, lower alkyl, lower alkoxy,lower alkanoyl or lower alkanoyloxy. The salts of the present inventioninclude the pharmaceutically acceptable sodium, potassium, calcium,magnesium, aluminum salts and the like.

The term lower alkyl as used herein means both cyclic and straightandbranched-chain saturated hydrocarbon radicals having from one to eightcarbons, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tbutyl, amyl, heXyl, cyclohexyl, Z-ethylcyclohexyl and the like.

Similarly, where the term lower is used as part of the description ofanother radical, e.g. lower alkoxy, it limits the alkyl portion of suchradical to such groups as were previously described in connection withlower alkyl.

Compounds within the scope of Formula I are useful as intermediates andreagents in the synthesis of other organic chemical compounds and asactive components in pharmaceutical formulations. The utility of thecompounds of Formula I as chemical reagents is derived primarily fromthe ability of the compounds to be N-brominated by adding bromine to asolution of the compound in ice-cold NaOH. The resulting N-bromoderivative having the characteristics of an N-bromo succinimide isuseful in the bromination of olefins by known methods. Thus, by themethod of Ziegler et al., Ann. 551, (1942), the unsaturated compound tobe brominated is heated with the N-bromo derivative in carbontetrachloride. As the bromination proceeds, the brominating agentseparates and can be filtered oil while the brominated olefin derivativecan be recovered by fractional distillation.

Compounds of Formula I can be used as the active component inpharmaceutical compositions since the compounds influence the activityof the central nervous system by the exertion of anti-convulsant,muscle-relaxant, anorexic and hypotensive activities. They also act asanalgesics. These activities can be demonstrated by standard testprocedures. For example, anorexic activity is demonstrated by the mouseanorexia assay. In this test, groups of five mice in each group, not fedfor the preceding sixteen to seventeen hours, are placed in a cage,given the drug to be tested and, after another thirty minutes, are givena weighed amount of food. One hour after presenting the food, the fooddish is removed and weighed. Control mice, i.e. dosed with water, eat anaverage of 6.2 grams per group of five mice. Significant anorexicactivity is exhibited when a group of five treated mice eat less thantwo grams in an hour when the preferred compound of the presentinvention, i.e. the compound of Formula I wherein R is isopropyl and Ris hydrogen, reduced the food intake to amounts in the range of 02 gramsat oral dosages of 25, 50 and mgm./kg.

The compounds of this invention may be administered as free bases or inthe form of their non-toxic salts. For therapeutic administration, thesecompounds may be admixed with pharmaceutical excipients and used, forinstance, in the form of tablets, dragees, capsules, suppositories,injectable liquids, liquids to be administered in drops, emulsions,suspensions, sirups, chocolate, candy, chewing gum, and the like. Suchcompositions and preparation should contain at least 0.1% of the activeingredient. The percentage in the compositions and preparations may, ofcourse, be varied and may conveniently be between about 2% and about 60%or more of the weight of the unit. The amount of active ingredient insuch therapeutically useful compositions or preparations is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention may be prepared in such a manner thata dosage unit form contains between about 10 milligrams and about 250miligrams of the novel compounds.

The compounds of Formula I can be prepared from known materials by thefollowing series of reactions:

(1) Malononitrile (II) and an aromatic ketone (III) are reacted by themethod of Mowry (J.A.C.S., 67, 1050 [1945]) to give anylidenemalononitrile (IV) as follows (Equation A):

-CR C=CCN 0112mm. R; l R1 II III IV Equation A (2) Theylidenemalononitrile (IV) is heated with a strong acid such asconcentrated sulfuric acid at a temperature of about 45-60 C. (method ofCampaigne et al., J. Org. Chem, 26, 4703, 1961) to give the indenones ofFormula V as follows (Equation B):

ll CI=(JCN Strong CONIIz(01-CN) R1 R ON acid RI R IV V Equation B (3)Cyanide addition to compounds of Formula V by treatment with excessaqueous alkali cyanide (optionally in an alcoholic solvent) and dilutesulfuric acid in the cold (method of Koelsch, J. Org. Chem., 25, 2088,1960), gives the 3-cyano-3-R-indanones of Formula VI as follows(Equation C):

(4) Treatment of compound VI with a concentrated strong acid such astechnical sulfuric acid (93.2%) at a temperature up to about 40 C.,gives the 2,3-dicarboxamido-l-indanone of Formula VII as follows(Equation D):

O 0 II II 11+ CONHz (01 CN) CONH: R1 R1 CN '-CONH1 R VI R VII Equation D(5) Compounds of Formula I are obtained from compounds of Formula VII byring closure with, for example, an organic solvent and a strong acid(e.g., diethylene glycol or ethylene glycol and technical grade sulfuricacid) at a temperature of about 120-130 C., as shown in the following(Equation E):

f i ring R1 closure O l CONHt I CONE: R

VII

Equation E In the foregoing formulae and equations, R and R are asdefined above. It will be noted that the 2-position of indenones ofFormula V and the indanones of Formula VI are indicated as beingalternatively substituted by either a carboxamido or a cyano group. Thisis because the cyano group of the precursor is not hydrolyzed when the Rradical of the precursor is a bulky group, e.g. t-butyl, but is hydratedwhen the R radical is a small group such as methyl or ethyl. In eitherevent, however, the hydrolysate of VI, i.e. compound VII, will have acarboxamido group in the 2-position of the indanone nucleus, as EquationD indicates.

Illustrative of the aromatic ketones (III) which can be converted by theforegoing reactions, are the following: benzophenone,p-chlorobenzophenone, p-methylbenzophenone,p-trifluoromethylacetophenone, p-ethoxypropiophenone,p-acetylacetophenone, p acetoxypropiophenone, butyrophenone,isobutyrophenone, cyclohexylphenylketone, hexylphenylketone, and thelike.

The following examples are presented to further illustrate the presentinvention.

Example 1.--2-carboxamido-3-cyano-3-ethyl-l-indanone A mixture of 10 g.(0.05 mole) of 2-carboxamido-3- ethyl-l-indenone, 4 g. (0.082 mole) ofsodium cyanide, 14 ml. of t-butyl alcohol and 40 ml. of water was heatedon a steam bath until a homogeneous solution was obtained (30 minutes)and poured into a mixture of 500 g. of ice and 15 ml. of 20% sulfuricacid, yielding a yellow oil. The oil was extracted with chloroform; thechloroform extract was washed with water and bicarbonate. Thebicarbonate wash was acidified, extracted with chloroform andevaporated, yielding the product as an oil.

Example 2.2-carboxamido-3-cyano-3- isopropyll-indanone A mixture of 20.0g. (0.093 mole) of 2-carboxamido-3- isopropyl-l-indenone, ml. of water,48 ml. of t-butyl alcohol and 8.0 g. (0.16 mole) of sodium cyanide washeated on a steam bath with stirring until a homogeneous solution wasobtained, then left at room temperature for three hours and poured intoa mixture of 600 g. of ice and 200 ml. of 20% sulfuric acid, yielding anoil. The oil was extracted with chloroform; the chloroform layer washedwith water, dried and evaporated, yielding an oil which solidified uponstanding, yielding 17.5 g. (78%) of a cream-colored solid, M.P. 100-110.Three recrystallizations from ethyl acetate-hexane afforded colorlessprisms, M.P. 136-137".

Example 3.-2,3-dicyano-3-t-butyll-indanone A mixture of 5.0 g. (24moles) of 2-cyano-3-t-butyl-lindenone, 20 ml. of water, 2.0 g. of sodiumcyanide (41 mmoles) and 2.0 ml. of t-butyl alcohol was warmed on a steambath until a clear red solution resulted (10 minutes). The solution wasadded with stirring to a mixture of 50 ml. of 20% sulfuric acid and 100g. of ice, yielding 5.6 g. (100%) of a pink precipitate, M.P. 133- 137".Two recrystallizations from benzene-petroleum ether (3:1) gave slightlypink plates, M.P. 140-142".

Example 4.-2-carboxamido-3-cyano-3-phenyl-l-indanone A mixture of 50.0g. (0.2 mole) of 2-carboxamido-3- phenyl-l-indenone, 200 ml. of water,20 g. of sodium cyanide (0.41 mole) and 20 ml. of ethanol was warmed ona steam bath until a clear solution resulted (12 minutes), the solutionwas cooled and acidified (by pouring into a mixture of 500 ml. of 20%sulfuric acid and 1 kg. of ice with stirring), yielding 54.5 g. (98%) ofa yellowish precipitate, M.P. 164-167 dec. Two recrystallizations fromethanol gave pink prisms, M.P. 171-173 Example5.2,3-dicarboxamido-3-ethyl-l-indanone The oil of Example 1 was added to100 ml. of technical (93.2%) sulfuric acid, the mixture heated on asteam bath until a homogeneous solution was obtained (20 minutes) andthen left at room temperature for minutes. The solution was poured onto1 l. of ice and extracted with chloroform; the chloroform extract waswashed with water, dried and evaporated, yielding 5.4 g. of a yellowsolid, M.P. 87l02. A small amount of this mixture was recrystallizedfrom ethanol, affording the product as yellowish prisms, M.P. 180-1815Example 6 .3 a-ethylsuccinimido 3,4-b indan-8-one A mixture of 5.0 g. ofthe product of Example 5, 50 ml. of diethylene glycol and 1 ml. ofconcentrated sulfuric acid was heated at -130 for 30 minutes and pouredinto 1 l. of ice, yielding 2.1 g. (42%) of a slightly tan precipitate,M.P. 178-179". Two recrystallizations from 95% ethanol gave prisms, M.P.181-182. The aqueous filtrate was extracted with chloroform, dried andevapo- Example 7 2,3-dicarboxamido-3-isopropyl-1-indanone A mixture of8.7 g. of the product of Example 2 and 100 ml. of concentrated sulfuricacid was stirred at room temperature for 80 minutes and poured into 1 l.of ice Water, yielding 7.7 g. (80%) of a white precipitate, M.P.165-168. Successive recrystallization from 95 ethanol, 30% ethanol andbenzene-petroleum ether (3:1) afforded Alternatively, the method of LeMoal for converting cyano carboxamides to succinimides can be employedas follows:

A mixture of 1.0 g. of the product of Example 3 and 25 ml. of a solutioncontaining 10% sulfuric acid, 70% acetic acid and 20% water was refluxedfor one hour, poured into 250 ml. of ice water and bicarbonate addeduntil the solution was basic. The basic solution was extracted withthree 50-rnl. portions of chloroform; the

10 chloroform extract dried and evaporated, yielding 0.15 sllghfly Pcrystals, g. (14%) of the product as a colorless precipitate. Example ppy Example 12.3 a-t-butylsuccinimido[3,4-b]-indan-8-one A mixture of 6.5g. of the product of Example 7, 50 ml. A mixture f 300 m of the productof Example 9, diethylene glycol and 1.2 ml. of concentrated sulfuric 155 1, f di h l glycgl d 5 drops of concentrated acid was heated at120-130 for 30 minutes and poure sulfuric acid was heated at 120-130 for15 minutes and into 600 Of ice Water, Yielding g- Of a poured into 50ml. of ice and water, yielding 210 mg.

yellowish precipitate, M.P. 232236. Two recrystallizaof the product as alight green precipitate, M.P.

tions from 95% ethanol afforded colorless needles, M.P. 188 196 236 2370 Example 13.-2,3-dicarboxamido-3-phenyl-l-indanone Example9.2,3-d1carboxam1do-3-t-butyl-l-lndanone A quantity of 20.0 g. of theproduct of Example 4 was Addition of of the Product Of EXample 3 f0 4added in portions to 80 ml. of concentrated sulfuric acid ofconcentrated Sulfuric acid. with stirring and the with stirring and thetemperature maintained below 40,

Peratnre maintained below minutes). gave a soluby intermittent coolingin an ice bath. After the addition tiOIl looked motor 011. The solutionwas stirred was complete (about 10 minutes) the mixture was tirred atroom temperature fOT minutes, Pollrfid into 40 at room temperature for1.5 hours, poured into 800 ml.

of ice Water and the precipitate allowfid to Settle Overnight, of icewater with stirring and allowed to settle overnight,

yielding 0.68 of an orange p pi 8 1 yielding 20.1 g. (95% of pinkmicrocrystals, M.P. 19s recrystallization from benzene-petroleum ether30 196". Recrystallization from 95% ethanol gave orange- (321) afforded0.23 g. (20%) of yellow crystals, M.P. pink prisms, M.P. 195-196".

153-155 dec. Two further crystallizations from benzene petroleum etherafforded colorless crystals, M.P. 1575- Example -P y 158.5 (aftermelting, it bub-bled, then resolidified and To a Slurry of 200 g. of theproduct of Example 13 melted at 220230 and .150 ml. of diethylene glycolwas added with stirring Example10.--3a-t-butylsuccinimido[3,4-b]-indan-8-one 5 ml. of concentratedsulfuric acid. The mixture was heated on a hot late with stirrin to 120a omo ene- The aqueous filtrate of Examp 1e 9 upon slttmg four ousviolet soluti z'in was obtaine at aboul: 80, vghich days, afforded 0.38g. (35%) of colorless crystals, M.P. o

231-234 Recr stallization from 50% ethanol afforded turned brown andfinally yenpw at about than th d i 1 s ris 8 MP 2434440 heated at 120130for 15 minutes, poured into 2 l. of epro uc as co or 6 SP m ice waterand allowed to settle overnight, yielding 117-8 Example1'l.3a-t-butylsuccinimido[3,4-b]-indan-8-one g- (94%) Of a Whiteprecipitate,

crystallization from ethanol (about 500 ml.) gave A mixture 0f of theProduct of example 3, 1 15.9 g. of the product as colorless needles,M.P. 180-18l.

of acetic acid and 2 ml. of concentrated sulfuric acid 4.5

was heated at 120-140" for 15 minutes and poured into E l 15 20 g. ofice, yielding 0.87 g. of a yellow powder, M.P.

147-148". Recrystallization from 50% ethanol afforded If the procedureof the foregoing examples is followed 0.20 g. (18%) of colorless prisms,M.P. 239-241; with except for the use of substituted indenones, thereare an infrared spectrum identical to that of the product of 50 obtainedthe correspondingly substituted 3a-substituted Example 10.succinimido[3,4-b]indan-8-ones as follows:

Example 16.-Anorexic activity In the mouse anorexia assay, the preferredcompound of the present invention,succinimido[3,4-b]-3a-isopropylindan-8-one, was elfective at 100, at 50and at 25 mgm./ kg. p.o. In this assay, groups of five mice not fed forthe preceding 16-17 hours, are placed in a cage, given the drug to betested, and after another thirty minutes, are given a weighed amount offood. One hour after presenting the food, the food dish is removed andweighed. Control mice, i.e. dosed with water, eat an average of 6.2 gm.per group of five mice. Significant anorexic activity is exhibited whena group of five treated mice eat less than 2 gm. in the hour. In varioustests, the preferred compound of the present invention reduced the foodintake to amounts in the range of 0-2 gm. at oral dosages of 25, 50 and100 mgm./kg.

We claim:

1. A compound of the formula:

wherein R is ethyl and R is hydrogen.

3. The compound of O 0 II II R mi -H wherein R is isopropyl and R ishydrogen.

8 4. The compound of wherein R is t-butyl and R is hydrogen.

5. The compound of wherein R is phenyl and R is hydrogen.

6. A process of preparing a compound of the formula:

0 0 II I N-H R1 References Cited FOREIGN PATENTS 11/1957 Great Britain.

OTHER REFERENCES Dey et 211.: Indian Journal of Chemistry, vol. 2, pages371-2 (1964). QDl, I65.

Weddleton Dissertation Abstracts, vol. 26, page 2488 (November 1965).AS30.M5.

HENRY R. JILES, Primary Examiner.

N. TROUSOF, Assistant Examiner.

US. Cl. X.R.

